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MYASTHENIA GRAVIS
Pakamas Pasogpakdee,MD6/28/09
Introduction
The most common primary disorder of neuromusculartransmission
Usual cause is an acquired immunological abnormality , somecases result from genetic abnormality at the NMJ
Women : 2nd and 3rd decades , Men : 6th decadesUSA : M>F (5th decades)
Neurology in Clinical Practice , 5th Edition , 20086/28/09
Immunopathology of MG
LEMS6/28/09
80% of MG pts. , weakness result from the effects ofcirculating anti-AChR Ab (T cell dependent)
destruction of the folds , accelerated internalization &destruction of AChR , block Ach-AchR binding
10% of MG pts. have circulating Ab to MuSKRemaining = seronegative
Neurology in Clinical Practice , 5th Edition , 2008
Immunopathology of MG
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Immunopathology of MG
AChR Ab +ve
AChR Ab neg
AntiMUSK
AntititinAb to ryanodine receptor
AntiRapsyn
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Clinical Presentation
65% ptosis & diplopia15% difficult chewing , swallowing , talking10% limb weakness rare single muscle group weaknessTypically fluctuates during the day , usually being least in themorning and worse as the day progresses , esp. after prolongeduse of affected muscles
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Clinical Presentation
Careful questioning often reveals evidence of earlier myasthenicmanifestration
- frequent purchases of new eyeglasses - avoidance of foods that became difficult to chew or swallow - cessation of activities that require prolonged use of specificm.
- friends may have noted a sleepy or sad facial appearance caused by ptosis or facial weakness
Neurology in Clinical Practice , 5th Edition , 20086/28/09
Physical Findings
pattern of muscle involvement Ocular muscle - eye movements - Eye lid Oropharyngeal muscle - "myasthenic snarl - nasal speech , difficulty chewing , difficulty swallowing
choking on liquids Limb muscle - Limb muscle weakness , Fatiguability
Neurology in Clinical Practice , 5th Edition , 20086/28/09
EYE & MG
Ptosis - usually asymmetrically - allow soap or water in the eyes during bathingDiplopia - Asymmetric weakness of several muscle in both eyes - Pattern of weakness is not characteristic of lesions of
one or more nerves
- Pupillary responses are normal - Weakness is most frequent & usually most severe in MRshould raise suspicion of MG in the combination of ptosis ,ophthalmoparesis , weak eye closure
Neurology in Clinical Practice , 5th Edition , 20086/28/09
Eyelid manifestation
Levator palpebrae - Ptosis - Upper eyelid retraction - Lid fatigue test - Enhancing ptosis - Cogan lid twitch sign - Ice test - Sleep test - Rest testOrbicularis oculi muscle - Forced eye closure: buried eyelashes
- Open the eyes against forced eyelid closure
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Upper eyelid retraction
Left upper eyelid retraction contralateral to a ptotic rightupper eyelid
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Lid fatigue test
(A) On initial upgaze, minimal left upper eyelid ptosis is evident(C) After 2 minutes of sustained upgaze, the degree of left
upper eyelid ptosis is significantly increased owing to levatormuscle fatigue
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Cogan lid twitch sign
looks down for at least 10 to 20 seconds makesan upward saccade back to primary gaze
transient overshoot of the upper eyelid , which maybe followed by nystagmoid twitches of the uppereyelid and then downward drifting of the eyelid to anormal or ptotic position
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Ice test
Preceding the test
An ice pack is applied to theclosed left eye for 2 minutes
Right upper eyelid ptosis issignificantly improved
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Sleep test
(A) before the test (B) After 30 minutes of sleep(lying down in a quiet and dimlylit room), the ptosis isnoticeably improved in botheyes
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Rest test
(A) Before rest (B) After only 5 minutes ofgentle eye closure, the ptosisis much improved in both eyes
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bilateral lagophthalmos
Not bury the eyelashes duringforced eye closure
Orbicularis oculi muscle
severe bilateral orbicularis weaknesssecondary lower eyelid retraction
weak orbicularis muscle in the right eye duringforced eye closure
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Ocular finding in myasthenia gravis
Weakness usually involves one or more ocular muscles w/o overt pupillary abnormality
Weakness is typically variable , fluctuating , fatigable
Ptosis that shifts from one eye to the other is virtually pathognomonic of MG
With limited ocular excursion , saccades are superfast , producing ocular quiver
After downgaze , upgaze produces lid overshoot lid twitch
Pseudo-internuclear ophthalmoplegia-limited adduction is present w/ nystagmoid jerks inabducting eye
In asymmetrical ptosis , covering the eye w/ the ptotic lid may relieve contraction of theopposite frontalis
Passively lifting a ptotic lid may cause the opposite lid to fall
Edrophonium may improve only one of several weak ocular muscle , other may becomeweaker
Edrophonium may relieve asymmetric ptosis & produce retraction of the opposite lid fromfrontalis contraction
The opposite lid may droop further as the more involved lid strengthens after edrophonium
Cold applied to the eye may improve lid ptosis Neurology in Clinical Practice , 5th Edition , 20086/28/09
Oropharyngeal Muscles
Changes in voice - nasal voice - asking high-pitched EEEEEEEEE sound Difficulty chewing and swallowing Inadequate maintenance of the upper airway Alter facial appearance
- myasthenic snarl
Neurology in Clinical Practice , 5th Edition , 20086/28/09
Myasthenic Snarl
Corner of mouthdroop downward
Rest Smile
Contraction of medial
portion of upper lip
No upward curling
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Trunk & limb muscles
Neck muscleUpper extremities
- Out stretched arms test - Grip fatigue can be measured with a dynamometer thatthe patient grasps repetitively - Repetitive exercise test
Lower extremity - step up and down from a footstool as if climbing stairs - progressively more difficult and the patient begins topush off their knee with their arm in order to help theweakening quadriceps
* Neck flexors , Deltoids , Triceps , WE , FE , ankledorsiflexors *
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Diagnostic test
Clinical diagnosis Investigation
Anticholinesterase test Autoantibodies Electridiagnosting Testing
repetitive nerve stimulation single-fibre electromyography
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Diagnostic test
1. Anticholinesterase test
Edrophonium Chloride (Tensilon) Test- Rapid onset(30sec), short duration(5min)
- 2 mg IV if no change add 8 mg IV
Neostigmine test
- Neostigmine 1-2 mg,IM- Effects seen within 20-40 min
- Should have measurable parameter eg. P tosis
Neurology in Clinical Practice , 5th Edition , 20086/28/09
Diagnostic test
1. Anticholinesterase test
False positive Edrophonium test
- Lambert-Eaton syndrome (37%positive)
- Botulism (27% positive)
- Congenital end-plate acetylcholine receptor deficiency
- Guillain-Barr syndrome
- Amyotrophic lateral sclerosis
- Brain stem glioma
Neurology in Clinical Practice , 5th Edition , 20086/28/09
Diagnostic test
2. Auto- Ab
serum antibodies that bind human AChR 70-90% generalized myasthenia 50-75% ocular myasthenia
AChR binding antibodies conc. sometimes increased inpatients w/
SLE , inflammatory neuropathy , ALS , RA taking D-penicillamine , thymoma w/o MG , normal relatives ofpatients with MG
Neurology in Clinical Practice , 5th Edition , 20086/28/09
Diagnostic test
2. Auto-Ab
Positive AChR Ab plus clinical = confirm diagnosis Negative AChR Ab can not be rule out no correlation between disease severity and antibody titre clinical improvement: associated with a fall in Ab titre
Biodrugs 2001 March; 15 (3): 173-83N Engl J Med 1994; 330 (25): 1797-810
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Diagnostic test
2. Auto-Ab
Anti-MUSK Ab Antistriational muscle Ab : predicting thymoma (60% of
pts. w/ MG w/ onset before age 50 have thymoma)
Others : Antititin Ab Anti ryanodine Ab
Neurology in Clinical Practice , 5th Edition , 20086/28/09
Diagnostic test
3. Electrodiagnostic test
Repetitive Nerve Stimulation (RNS) - Decrement of > 10% at 3 Hz: highly probable - more often in proximal muscles, such as
the facial muscles, biceps, deltoid, and trapezius than inhand muscles
- Anti-ChE medications should withheld 12hours (24 hours) prior to testing
- Yield of RNS : Ocular MG 30-40% Generalized MG 70-80%
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Diagnostic test
3. Electrodiagnostic test
Single Fiber EMG (SFEMG) - most sensitive clinical test of neuromuscular
transmission
- shows increased jitter in some muscles inalmost all patients with myasthenia gravis
- positive in 95-99% of pts. with generalized MG
Neurology in Clinical Practice , 5th Edition , 20086/28/09
Diagnostic test
Anticholinesterase test : often Dx in pts. w/ ptosis orophthalmoparesis , less useful in assessing other muscles
Autoantibodies : presence of AChR-Ab , anti-MUSK Ab ensuresthe Dx of MG , but absence dose not exclude
Electrodiagnosting Testing repetitive nerve stimulation : confirm impaired
neuromuscular transmission , but frequently normal inmild or purely ocular disease
single-fibre electromyography : normal jitter in weakmuscle excludes MG
Neither EDx is specific for MGNeurology in Clinical Practice , 5th Edition , 20086/28/09
Sensitivity of tests in MG
Tests Ocular MG Generalized MG
Edrophonium test 80-90% 80-90%
Ice pack / sleep test Criteria poorly defined Criteria poorly defined
AChR Ab 30-50% 80-90%
MuSK Ab Rare 30-40% of seronegative
Antistriatal Ab 80% in pt. w/ thymoma
30% in pt. w/o thymoma
80% in pt. w/ thymoma
30% in pt. w/o thymoma
RNS 30-60% 90%
Single fiber EMG 90-95% 90-95%
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DDx : Ocular MG
Mitochondrial disorder : CPEOOculopharyngeal muscular dystrophyThyroid ophthalmopathyBrainstem lesionLocal eyelid disorder
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DDx : Generalized MG
NMJ disorder - LEM - Congenital myasthenic syndrome - Neurotoxins eg. BotulismMyopathiesDemyelinating polyneuropathies
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Assessment
Associated disorder - Disorder of thymus : Thymoma , Hyperplasia - Other autoimmune disorder : Hashimoto thyroiditis ,
Graves disease , RA , SLE
Disorder or circumstance that may exacerbate MG - Hyperthyroidism , Occult infection - Medical Rx of other condition (aminoglycoside,
quinidine, antiarrhythmic drug)
Disorder that may interfere therapy - TB , DM , PU , GI bleed , Asthma , osteoporosis
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Classification (modifications of Osserman)
Class I - Ocular myasthenia
Class IIA - Mild generalized myasthenia with slow progression;no prominent bulbar signs; no crisis; drug responsive
Class IIB - Moderate generalized myasthenia; severe skeletaland bulbar involvement but no crisis;
drug response than satisfactory
Class III - Acute fulminating myasthenia; rapid progression ofsevere symptoms with respiratory crisis and poor
drug response; high incidence of thymoma; high mortality
Class IV - Late severe myasthenia; same as III but progress
over two years from class I to II6/28/09
Class I - Any ocular muscle weakness- May have weakness of eye closure- All other muscle strength is normal
Class II - Mild weaknessaffecting other than ocular muscles- May also have ocular muscle weakness of any severity
IIa - Predominantly affecting limb , axial muscles , or both- May also have lesser involvement of oropharyngeal
IIb - Predominantly affecting oropharyngeal ,respiratorymuscles or both
- May also have lesser or equal involvement of limb , axial
muscles or both
Classification (MGFA)
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Class III-Moderate weaknessaffecting other than ocular muscles- May also have ocular muscle weakness of any severity
IIIa - Predominantly affecting limb , axial muscles , or both- May also have lesser involvement of oropharyngeal
IIIb - Predominantly affecting oropharyngeal ,respiratorymuscles or both
- May also have lesser or equal involvement of limb , axialmuscles or both
Classification (MGFA)
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Class IV- Severe weaknessaffecting other than ocular muscles- May also have ocular muscle weakness of any severity
IVa - Predominantly affecting limb , axial muscles , or both- May also have lesser involvement of oropharyngeal
IVb - Predominantly affecting oropharyngeal ,respiratorymuscles or both
- May also have lesser or equal involvement of limb , axialmuscles or both
Class V - Defined by intubation, w/ or w/o mechanical ventilationexcept when employed during routine postoperativemanagement
The use of a feeding tube w/o intubation places the patients in class IVb
Classification (MGFA)
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Classification (MGFA)
Class IV- Severe weaknessaffecting other than ocular muscles- May also have ocular muscle weakness of any severity
IIIa - Predominantly affecting limb , axial muscles , or both- May also have lesser involvement of oropharyngeal
IIIb - Predominantly affecting oropharyngeal ,respiratorymuscles or both
- May also have lesser or equal involvement of limb , axialmuscles or both
Class V - Defined by intubation, w/ or w/o mechanical ventilationexcept when employed during routine postoperativemanagement
The use of a feeding tube w/o intubation places the patients in class IVb
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Clinical subtypes
Early onset cases Late onset cases Ocular myasthenia Seronegative MG
Thymoma associated MG Positive antititin antibodies
Neonatal MG
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Early onset cases
Female Onset before age 40 AChR Ab-positive Usually do not Ab to muscle Ag Hyperplasia of thymus gland 60% of cases : HLA-D8 , HLA-DRw3
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Late onset cases
Men slightly more than female Onset after age 40 Associated with HLA-B7 , HLA-DRw2
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Ocular myasthenia
AChR Ab positive only 40-60% of cases Represent mild cases of autoimmune generalized MG 50-60% develop generalized weakness in 1-2 years 40% remain ocular MG Pts. w/ pure ocular symptoms for 2 yrs. have less
chance to develop generalized MG
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Seronegative MG
Clinicla similar to MG with AChR Ab Many evidence suggest autoimmune in origin
Development of neonatal MG in babies born toseronegative mother
Response to plasma exchange A good proportion of cases have autoantibodies to a
muscle specific receptor tyrosine kinase (MuSK)
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Thymus & MG
more mature T cells than normal Thymus70% of pt. have lymphoid follicular hyperplasia> 10% of pt. have a thymoma3060% of thymomas associated with MG
Neurology in Clinical Practice , 5th Edition , 20086/28/09
TREATMENT
Controlled clinical trials : rareObjectives :
Directly target autoimmune responseModify Ab production or modify immune mediated damageto NMJ
Modify natural history of diseaseStrategy : induce remission , maintain remission
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TREATMENT
CSR: no s/s of MG 1 yr. & has received no therapy for MGduring that time , isolated weakness of eyelid closure is accept
PR: same criteria of CSR except that the pts. continue to takesome from of therapy of MG. Pts. taking
cholinesterase inh. are excluded from this category because theiruse suggests the presence of weakness
CSR = complete stable remission , PR = pharmacologic remission
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TREATMENT
MM : no symptoms of functional limitation from MG , someweakness on examination of some muscles
MM-0 : no MG treatment 1 yr.MM-1 : receive some form of immunosuppression , no ChE
inhibitor or other symptomatic therapy
MM-2 : receive low dose of ChE inhibitor(
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SYMPTOMATIC TREATMENTS
Pharmacologic treatmentCholinesterase inhibitor (first line medication)
Muscle training , weight control , lifestyle modification
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Cholinesterase inhibitor
retard the enzymatic hydrolysis of ACh at cholinergicsynapses ACh accumulates at NMJ prolonged effects
diagnostic testearly treatment , symptomatic treatment response usually becomes less w/ chronic use
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Cholinesterase inhibitor
Pyridostigmine bromide (Mestinon) & neostigmine bromide(Prostigmine)
initial oral dose = 30-60 mg every 4-6 hrs.mestinon 60 mg , oral = neostigmine methylsulfate 0.5mg , IV
no fixed dosage schedule suits all patientsvaries from day to day & during the same daydifferent muscles response differently
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Cholinesterase inhibitor
Drugs schedule should be titrated to produce an optimalresponse in muscles causing the greatest disability
Attempts to eliminate all weakness by increasing thedose or shortening the interval causes overdose at the timeof peak effect
keep the dose low enough to provide definiteimprovement in the most important muscle groupsw/in 30-45 min , expect the effect to wear offbefore the next dose
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Cholinesterase inhibitor
Adverse effect : muscarinic receptor on smooth muscle &autonomic glands
nicotinic receptor on skeletal musclecommon : GI queasiness , nausea , vomiting ,abdominal cramp , loose stool , diarrhea
suppress with loperamide hydrochloride(Imodium) ,propantheline bromide(Pro-Banthine) ,glycopyrrolate(Robinul) diphenoxylate hydrochloride w/atropine(Lomotil)
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Corticosteroids Immunosuppressant drugsPlasma exchange Intravenous immunoglobulinThymectomy
IMMUNOMODULATION
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G0=dormant phase
G1= resting phase
M= mitotic ph ase
G2= perimitotic phase
S= DNA synthesisphase
CY
CY
CY
CY , AZAMMF , MTX
CY , AZAMMF , MTX
Cell cycle
IMMUNOMODULATION
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T cellNucleus
T-cell receptor
T-cell receptorMacrophage
Extracellular
Intracellular
S
S
CSA
TAC
IMMUNOMODULATION
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Corticosteroids
Mechanism :Blocking Ag processingDecrease number of circulating T cellsReducing trafficking of inflammatory cellsReduce expression of inflammatory cytokines and adhesionmolecules
Never been studied in large RCT marked improvement orcomplete relief of symptoms > 75% of pts.onset : 6-8 weeks remission : 3 monthsgood response : pts w/ recent onset of symptoms
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Corticosteroids
1.5-2.0 mg/kg/day until sustained improvement (2 wks.)EOD
reduced 20 mg/mo. 60 mg , EOD reduced 10 mg/mo. 20 mg , EOD reduced 5 mg q 3 mo 10 mg , EODnot reduce the dose further than this unless anotherimmunosuppressant being given
weakness returns increased dosage or addimmunosuppressant
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Corticosteroids
1/3 of pts. become weaker temporarily , usually in first 7-10days
managed w/ ChE inhibitorsoropharyngeal weakness or respiratory insufficiency : plasmaexchange before started prednisone
should be hospitalized to start this treatment
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Corticosteroids
start 20 mg/day increase 10 mg q 1-2 wks. maximumimprovement
reduced as above reduced frequency or severity of corticosteroid-inducedexacerbations
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Corticosteroids
SE : hypercorticism , weight gain , HT , diabetes ,anxiety / depression / insomnia steroid psychosis ,glaucoma , osteoporosis , cataracts , ulcer/GI perforations ,myopathy , opportunistic infections , avascular necrosis oflarge joints
SE increased when high daily dose > 1 mo.SE resolved when taper dose , 2x discontinue restart when values become normalpancreatitis : rarepotentially mutagenic adequate contraception
Azathioprine
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Cyclosporine (CYA)
Retrospective analyses :
improvement in most pts. taking CYA w/ or w/ocorticosteroids
Ciafaloni et al. 20006/28/09
inhibits predominantly T-lymphocyte dependent immuneresponse
start at 5-6 mg/kg/day (divided 12 hr. apart)measured serum level at 1 mo.keep trough serum CYA concentration 75-150 ng/mLmonitor serum creatinine q 2-3 mo.
Cyclosporine (CYA)
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SE : renal toxicity , HTN improve 1-2 mo. , maximum improvement after 6 mo.after maximum response gradually reduced CYA tominimum that maintain improvement
Cyclosporine (CYA)
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Cyclophosphamide
given IV in monthly pulsed doses has been used
effectively in severe , generalized MG that is refractory to
other therapy
De Feo et al ,2002 Drachman et al,20026/28/09
IV : 500 mg/m2oral : 150-200 mg/day total dose 5-10 gSE : alopecia , cystitis , nausea , vomiting , anorexia ,discoloration of nail & skin
Cyclophosphamide
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Mycophenolate mofetil (MM)
inhibits the proliferation of B & T-lymphocyte clones ,responding to antigenic stimulation
suppresses the formation of Ab active in complement-dependent lysis & cell-mediated cytotoxicity
2 g/day in divided 12 hr. apartonset action : 2 wks.SE : leukopenia , diarrhea refractory MG , as corticosteroid sparing agent whenazathioprine has produced intolerable SE or has not beeneffective
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Mycophenolate mofetil (MM)
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Mycophenolate mofetil (MM)
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Plasma Exchange
sudden worsening of myasthenic symptoms for any reason rapidly improve strength before surgeryconcomitantly w/ starting high dose corticosteroidschronic intermittent treatment for refractory MG
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Plasma Exchange
remove 2-3 Liters of plasma , 3 times a wk. untilimprovement , usually 5-6 exchanges
improvement usually begin after 2nd or 3rd exchange improvement last for wks or months repeated exchange not produce a cumulative benefitSE : cardiac arrythmias , nausea , lightheadedness , chills ,obscured vision , pedal edema
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Intravenous Immunoglobulin
2 g/kg (0.4 g/kg/day) infused over 2-5 days improvement 50-100% , begin in 1 wk. , lasting for severalwks. or mo.
SE : headache , chills , fever , alopecia , aseptic meningitis ,leukopenia , retinal necrosis , renal failure , cerebralinfarction , myocardial infarction
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Intravenous Immunoglobulin
C/I : selective IgA deficiency because may develop anaphylaxis to IgA in IVIg preperation A multicenter , randomized , controlled s tudy comparingplasmapheresis with IVIg has demonstrated equal efficacy butsignificanly fewer and less severe SE for IVIg
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Thymectomy
classic long-term treatmenteffect is usually not apparent until after 1 yr , and the fulleffect is not felt for 5 yr
never been demonstrated to be effective in a prospective ,controlled study
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Thymectomy
Controversies
Effectiveness in late onset pts. (>50 year old)Reduced effectiveness in MuSK +ve patientsCost effectivenessWhen to performed thymectomyWhich surgical techniques
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Thymectomy
American Academy of Neurology : medication free remission : 2x
asymptomatic : 1.6x show improvement : 1.7x For pts. w/ nonthymomatous autoimmune MG ,thymectomy is recommended as an option to increase theprobability of remission or improvement
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Thymectomy
recommended thymectomy for most pts. w/ MG whosesymptoms begin before age 60
good response : young people , women , early in course ofdisease
advantage : induce sustained , drug-free remission , removethymoma
transthoracic approach
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Thymectomy
repeat thymectomy :chronic refractory diseaseall thymic tissue not removed at prior surgerygood response to original surgery
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Ocular MG
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MG (II,III,IV)
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Factor that worsen myasthenic symptoms
emotional upsetsystemic illness (esp. viral respiratory infections)
hypothyroidism or hyperthyroidismpregnancymenstrual cycle
DrugsFever
Neurology in Clinical Practice , 5th Edition , 2008
Special situations
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Special situations
Surgery : spinal block avoidance neuromuscular blocking agentPregnancy :
improve-stable-worse ChE inhibitor induce uterine contraction
immunosuppressant : only corticosteroids transient neonatal myasthenia
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Special situations
Avoidance of situations in which neuromuscular transmissionmay be compromised
Penicillamine , amiodarone , aminoglycosides
thyroid dysfunction may have direct effect on the NMJ
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Prognosis
course of disease : variable but usually progressiveocular myasthenia generalized myasthenia (2 years) , 1st yearmaximum weakness (65%)
active stage : symptoms fluctuate over a relatively short period andthen become more severe
burnt-out stage : after 15-20 years , untreated weakness becomefixed , muscle atrophy
remission : may occur early on but rarely permanentNeurology in Clinical Practice , 5th Edition , 20086/28/09